HEDGEHOG/GLI Modulates the PRR11-SKA2 Bidirectional Transcription Unit in Lung Squamous Cell Carcinomas

Abstract

We previously demonstrated that proline-rich protein 11 (PRR11) and spindle and kinetochore associated 2 (SKA2) constituted a head-to-head gene pair driven by a prototypical bidirectional promoter. This gene pair synergistically promoted the development of non-small cell lung cancer. However, the signaling pathways leading to the ectopic expression of this gene pair remains obscure. In the present study, we first analyzed the lung squamous cell carcinoma (LSCC) relevant RNA sequencing data from The Cancer Genome Atlas (TCGA) database using the correlation analysis of gene expression and gene set enrichment analysis (GSEA), which revealed that the PRR11-SKA2 correlated gene list highly resembled the Hedgehog (Hh) pathway activation-related gene set. Subsequently, GLI1/2 inhibitor GANT-61 or GLI1/2-siRNA inhibited the Hh pathway of LSCC cells, concomitantly decreasing the expression levels of PRR11 and SKA2. Furthermore, the mRNA expression profile of LSCC cells treated with GANT-61 was detected using RNA sequencing, displaying 397 differentially expressed genes (203 upregulated genes and 194 downregulated genes). Out of them, one gene set, including BIRC5, NCAPG, CCNB2, and BUB1, was involved in cell division and interacted with both PRR11 and SKA2. These genes were verified as the downregulated genes via RT-PCR and their high expression significantly correlated with the shorter overall survival of LSCC patients. Taken together, our results indicate that GLI1/2 mediates the expression of the PRR11-SKA2-centric gene set that serves as an unfavorable prognostic indicator for LSCC patients, potentializing new combinatorial diagnostic and therapeutic strategies in LSCC.

Clinical significance and effect of PRR 11 up-regulation on the malignancy of osteosarcoma

“…Univariate and multivariate analysis showed that PRR11 was an independent prognostic factor for squamous cell carcinoma of the tongue [24]. In accordance with the TCGA database, the present study found that PRR11 had a significant effect on the survival rate of osteosarcoma, and the Regarding the mechanism by which PRR11 promotes tumor progression, many bioinformatics studies have shown that PRR11 is mainly involved in regulation of the cell cycle, M phase, and mitotic cell cycle, and in various tumor signaling pathways [25][26][27]. In addition, a large number of cell experiments have also shown that PRR11 affects cell migration, proliferation, and invasion in a variety of tumors.…”

Bioinformatic analysis of the obesity paradox and possible associated factors in colorectal cancer using TCGA cohorts

“…Additionally, the transcriptional regulatory mechanisms of SKA2 gene were investigated, previous studies revealed that some transcription factors such as NF-Y (nuclear transcription factor Y), CREB (cyclic AMP responsive element-binding protein), NF-κΒ, and p53, non-coding RNAs including miR-301, miR-141 and Circ_0008039, and Hedgehog pathway member GLI1/2, are implicated in dysregulation of SKA2 expression and contributed to tumor development [11,[14][15][16][17][18]. Nevertheless, downstream genes regulated by SKA2 in cancer cells are still vacant.…”

SKA2-mediated transcriptional downregulation of the key enzyme of CoQ10 biosynthesis PDSS2 in lung cancer cells

“…Taken together, aberrant expression of SKA2 is associated with tumor progression. Additionally, the transcriptional regulatory mechanisms of SKA2 gene were investigated, previous studies revealed that some transcription factors such as NF-Y (nuclear transcription factor Y), CREB (cyclic AMP responsive element-binding protein), NF-κΒ, and p53, non-coding RNAs including miR-301, miR-141 and Circ_0008039, and Hedgehog pathway member GLI1/2, are implicated in dysregulation of SKA2 expression and contributed to tumor development 11 , 14 - 18 . Nevertheless, downstream genes regulated by SKA2 in cancer cells are still vacant.…”